Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study
Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study
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DOI：
10.1093/hmg/ddi187
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Munroe, PB
中科院分区：
文献类型：
--
作者：
Newhouse, SJ;Wallace, C;Munroe, PB
WNK1基因突变导致戈登综合征，这是一种罕见的孟德尔式高血压。我们评估了常见的WNK1变异是否也可能导致原发性高血压（EH），这是一种影响全球25%成人人口的多因素疾病。从公共数据库中选择了19个跨越该基因的单核苷酸多态性（SNPs），并对100个欧洲白人家庭进行了基因分型，以确定WNK1位点的连锁不平衡模式、单倍型结构和标记SNPs。8个标记snp被鉴定出来，预测常见WNK1单倍型和snp的准确率为90%。基于家族的关联试验用于检测来自MRC英国高血压遗传学研究资源的712个严重高血压家族与EH和高血压严重程度的关联。未发现WNK1多态性或单倍型与高血压相关；然而，一个SNP rs1468326，位于WNK1启动子3 kb处，被发现与高血压的严重程度有关，收缩压（BP） （Z = + 2.24, P = 0.025）和舒张压（Z = + 1.99, P = 0.046）。我们还发现一种常见的WNK1单倍型与收缩压升高有名义上的关联（Z = + 1.91, P = 0.053）。这是第一个对WNK1基因与EH进行单倍型关联分析的研究。这一发现表明，启动子区域附近的SNP与高血压的严重程度之间存在关联，这表明WNK1表达的增加可能有助于BP变异性和对EH的易感性，这与戈登综合征中观察到的高血压机制相似。
Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting >25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spanning the gene was selected from public databases and was genotyped in 100 white European families to determine the pattern of linkage disequilibrium, haplotype structure and tagging SNPs for the WNK1 locus. Eight tagging SNPs were identified with 90% power to predict common WNK1 haplotypes and SNPs. Family-based association tests were used to test for association with EH and severity of hypertension in 712 severely hypertensive families from the MRC British Genetics of Hypertension study resource. No association was found between WNK1 polymorphisms or haplotypes with hypertension; however, one SNP rs1468326, located 3 kb from the WNK1 promoter, was found to be nominally associated with severity of hypertension, with both systolic blood pressure (BP) (Z = + 2.24, P = 0.025) and diastolic BP (Z = + 1.99, P = 0.046). We also found nominal support for association of one common WNK1 haplotype with increased systolic BP (Z = + 1.91, P = 0.053). This is the first study to perform haplotype association analysis of the WNK1 gene with EH. This finding of association between a SNP near the promoter region and the severity of hypertension suggests that increased expression of WNK1 might contribute to BP variability and susceptibility to EH similar to the mechanism of hypertension observed in Gordon's syndrome.